83 research outputs found
Recent advances in NAFLD: current areas of contention
No full textThis brief review focuses on two contentious issues within the field of non-alcoholic fatty liver disease (NAFLD); the first is the recent effort to redefine NAFLD as metabolic (dysfunction)-associated fatty liver disease (MAFLD). The modification of “NAFLD” to “MAFLD” is expected to highlight the role of metabolic factors in the disease aetiology, which is hoped to improve patient understanding of the disease, facilitate patient-physician communication and highlight the importance of public health interventions in prevention and management. The diagnostic criteria for MAFLD allow it to coexist with other forms of liver disease, which recognises that metabolic dysfunction contributes towards disease progression in other liver pathologies, such as alcoholic liver disease. However, there remain concerns that renaming NAFLD may be premature without fully considering the broader implications, from diagnostic criteria to trial endpoints; therefore, the new definition has not yet been accepted by major societies. Another contentious issue within the field is the gap in our understanding of how patients undergoing therapeutic interventions should be monitored to assess amelioration/attenuation or the worsening of their liver disease. Biomarker scoring systems (such as the ELF test and FIB-4 test) and imaging techniques (such as transient elastography [TE] and magnetic resonance imaging [MRI] techniques) are proven to be reasonably accurate, and comparable with histology, in the diagnosis of NAFLD and evaluation of disease severity; however, their use in monitoring the response of disease to therapeutic interventions is not well established. Whilst biomarker scoring systems and TE are limited by poor diagnostic accuracy in detecting moderate fibrosis (e.g. F2 liver fibrosis defined by histology), more accurate MRI techniques are not practical for routine patient follow-up due to their expense and limited availability. More work is required to determine the most appropriate method by which therapeutic interventions for NAFLD should be monitored in clinical practice.<br/
The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease
No full textNon-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.</p
Diagnosis and management of non-alcoholic fatty liver disease
No full textNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries. The prevalence of NAFLD is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. NAFLD represents a spectrum of liver disease severity. NAFLD begins with accumulation of triacylglycerols in the liver (steatosis), and is defined by hepatic fatty infiltration amounting to greater than 5% by liver weight or the presence of over 5% of hepatocytes loaded with large fat vacuoles. In almost a quarter of affected individuals, steatosis progresses with the development of liver inflammation to non-alcoholic steatohepatitis (NASH). NASH is a potentially progressive liver condition and with ongoing liver injury and cell death can result in fibrosis. Progressive liver fibrosis may lead to the development of cirrhosis in a small proportion of patients. With the growing prevalence of NAFLD, there is an increasing need for a robust, accurate and non-invasive approach to diagnosing the different stages of this condition. This review will focus on (1) the biochemical tests and imaging techniques used to diagnose the different stages of NAFLD; and (2) a selection of the current management approaches focusing on lifestyle interventions and pharmacological therapies for NAFLD
Down East Bookshelf. Book review of Limerock: Maine Stories by Christopher
No full textDown East Bookshelf. Book review of Limerock: Maine Stories by Christopher Fahy, and brief reviews of Railroads of the Pine Tree State by Don Marson and Brian Jennison; Natural Things: Collected Poems 1969-1998 by Constance Harting; and The Cow on the Spruce, one of Maine\u27s finest novels, written in 1946 by Chenoweth Hall
Adaptive sample size modification in clinical trials:start small then ask for more?
No full textWe consider sample size re-estimation in a clinical trial, in particular when there is a significant delay before the measurement of patient response. Mehta and Pocock have proposed methods in which sample size is increased when interim results fall in a "promising zone" where it is deemed worthwhile to increase conditional power by adding more subjects. Our analysis reveals potential pitfalls in applying this approach. Mehta and Pocock use results of Chen, DeMets and Lan to identify when increasing sample size but applying a conventional level alpha significance test at the end of the trial does not inflate the type I error rate: we have found the greatest gains in power per additional observation are liable to lie outside the region defined by this method. Mehta and Pocock increase sample size to achieve a particular conditional power, calculated under the current estimate of treatment effect: this leads to high increases in sample size for a small range of interim outcomes, whereas we have found it more efficient to make moderate increases in sample size over a wider range of cases. If the above pitfalls are avoided, we believe the broad framework proposed by Mehta and Pocock is valuable for clinical trial design. Working in this framework, we propose sample size rules which apply explicitly the principle of adding observations when they are most beneficial. The resulting trial designs are closely related to efficient group sequential tests for a delayed response proposed by Hampson and Jennison
Smith Bridge Company, Toledo, Ohio, 1888
No full textPhoto shows some of the employees of the Smith Bridge Company in front of the company's office in East Toledo. This photo was taken in 1888. The men in the photo are identified from left to right as follows: D. Howell, Christopher Gates, J. Ferdinand Zwilling, M. J. Riggs, W. H. Smith, William S. Daly, Robert Barber, Albert Masters, William A. Howell, Harry Jennison, W. F. Johnston, and George Crafts. Terms associated with the photograph are: Gates, Christopher | Zwilling, J. Ferdinand | Riggs, M. J. | Daly, William S. | Barber, Robert | Masters, Albert | Howell, William A. | Jennison, Harry | Johnston, W. F. | buildings | factory | Smith Bridge Company (Toledo, Ohio) | East Toledo (Toledo, Ohio) | Howell, D. | Smith, W. H. | Crafts, Georg
Comment: Group Sequential Designs with Response-Adaptive Randomisation
No full textGroup sequential Phase III trial designs enable early stopping for positive or negative study outcomes. Response-adaptive randomisation can be included in such designs with the sampling ratio in each group of subjects determined by the current treatment effect estimate. We demonstrate the potential of adaptive randomisation to reduce the number of patients receiving the inferior treatment, even when there is a delay in observing each patient’s response. We also observe that using a fixed but unequal sampling ratio may offer a simpler way to achieve the same objectives.</p
Adaptive and nonadaptive group sequential tests
No full textMethods have been proposed for redesigning a clinical trial at an interim stage in order to increase power. In order to preserve the type I error rate, methods for unplanned design-change have to be defined in terms of nonsufficient statistics, and this calls into question their efficiency and the credibility of conclusions reached. We evaluate schemes for adaptive redesign, extending the theoretical arguments for use of sufficient statistics of Tsiatis & Mehta (2003) and assessing the possible benefits of preplanned adaptive designs by numerical computation of optimal tests; these optimal adaptive designs are concrete examples of optimal sequentially planned sequential tests proposed by Schmitz (1993). We conclude that the flexibility of unplanned adaptive designs comes at a price and we recommend that the appropriate power for a study should be determined as thoroughly as possible at the outset. Then, standard error-spending tests, possibly with unevenly spaced analyses, provide efficient designs, but it is still possible to fall back on flexible methods for redesign should study objective change unexpectedly once the trial is under way. Copyright 2006, Oxford University Press.
Bootstrap Tests and Confidence Intervals for a Hazard Ratio When the Number of Observed Failures is Small, With Applications to Group Sequential Survival Studies
No full textGroup sequential tests for delayed responses
No full textGroup sequential methods are used routinely to monitor clinical trials and to provide early stopping when there is evidence of a treatment effect, lack of an effect, or concerns about patient safety. In many studies, the response of clinical interest is measured some time after the start of treatment and there are subjects at each interim analysis who have been treated but are yet to respond. We formulate a new form of group sequential test which gives a proper treatment of these "pipeline" subjects; these tests can be applied even when the continued accrual of data after the decision to stop the trial is unexpected. We illustrate our methods through a series of examples. We define error spending versions of these new designs which handle unpredictable group sizes and provide an information monitoring framework that can accommodate nuisance parameters, such as an unknown response variance. By studying optimal versions of our new designs, we show how the benefits of lower expected sample size normally achieved by a group sequential test are reduced when there is a delay in response. The loss of efficiency for larger delays can be ameliorated by incorporating data on a correlated short-term endpoint, fitting a joint model for the two endpoints but still making inferences on the original, longer term endpoint. We derive p-values and confidence intervals on termination of our new tests
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